Abstract B102: Zibotentan (ZD4054), a specific antagonist of the endothelin A receptor, suppresses the metastatic phenotype of bladder cancer cells in vivo

Abstract

There is mounting evidence that endothelin-1(ET-1) / endothelin receptor axis contributes to the pathogenesis of urothelial bladder cancer. In a previous study, reduced expression of the metastasis suppressor protein RhoGDI2 in bladder cancer cell lines and tumors was associated with increased expression of ET-1 (Titus B et al, Ca Res 65:7320, 2005). This suggests that ET-1 acts down-stream of repressed RhoGDI2 expression to promote the metastatic phenotype. If so, then blocking activation of endothelin receptor A (ETAR) by ET-1 would suppress this phenotype. To test this hypothesis, Zibotentan, a specific inhibitor of ETAR (IC50 = 21 nM), was evaluated for anti-tumor activity in a xenograft metastasis model. To screen for toxicity, 40 athymic nu/nu female received 12.5 to 50 mg/kg/d of zibotentan by gastric lavage for 97 days. The drug was well tolerated at all dose levels and produced no significant changes in body weight, behavior, or general physical condition. In a separate experiment, T24T bladder cancer cells (106 cells suspended in 0.1 mL of medium) were inoculated into the tail veins of a second group of 40 mice. One week later, 20 of animals were treated with zibotentan 50 mg/Kg/d and 20 controls received vehicle only. After 90 days, the animals were euthanized and the lungs were removed, fixed with Bouin's solution, stained, and examined by microscopy to determine the number and size of metastasis (large ≥3mm, small <3mm). Metastases were found in 12/20 (60%) controls and 3/20 (15%) of treated mice (p=0.024); overall, 89 metastases were identified in the controls and 19 in the treated animals (p=0.012). Although the drug-treated mice had fewer metastases, 13/19 (68%) of these were classified as large tumors as compared to 20/89 (22%) in the control group. These results suggest that inhibition of ETAR signaling by zibotentan reduced the frequency and number of metastases, most likely by suppressing metastatic colonization rather than the growth of established metastases. The latter is consistent with earlier data that inhibition of ETAR does not block the proliferation of T24T cells in vitro. Taken together, these and the previous observations provide a rationale for clinical trials to determine if treatment with zibotentan will prevent or delay the development of metastatic disease in patients with clinically localized but high-risk bladder cancer. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B102.

MicroRNAs as Novel Biomarkers in Colorectal Cancer

“…Involved miRNAs are indicated, together with assigned miRNA UP-(↑) or DOWN-(↓) regulation. Modified from Slaby et al (2009), Vilar et al (2011), Valeri et al (2009), and Zarate et al (2012). …”